This application seeks to challenge current approaches to treating drug dependence by investigating the idea of neurobiological readiness for treatment. This notion is analogous to the behavioral stages of change conceptualized in the field of psychotherapy and already applied to substance abuse treatment, but here it refers to objective indicators of the brain's ability to respond to medication at a specific point during recovery. The proposed project will focus on the cocaine-GABA relationship as an exemplar because no FDA-approved pharmacotherapeutics exist for treating cocaine dependence, but a number of candidate medications targeting the GABA system are under investigation. While the strategy of boosting GABA activity pharmacologically is supported by a significant body of evidence implicating GABAergic dysfunction in the etiology of cocaine dependence, we believe its modest success to date is due to the one-size-fits-all approach that assumes cocaine-related GABAergic impairment is stable over the stages of recovery. We challenge this by asking, how do GABA levels change when the brain has an opportunity to readjust after drug exposure ceases? Also, how does the GABA baseline affect the brain's ability to respond to treatment with GABAergic medications? The primary goal of this project is to address these gaps in our knowledge that we believe represent barriers to treatment. To accomplish this goal, we will assess proton magnetic resonance spectroscopy (1H MRS) and blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) correlates of GABAergic function longitudinally during an incentivized abstinence period in non-treatment-seeking cocaine-dependent volunteers. The first aim will establish the timeline of cocaine abstinence-related changes in GABA levels by tracking GABA during active exposure and through both early and prolonged abstinence. The second aim will demonstrate the dynamic nature of GABAergic responsivity over the same time course by probing the system with a GABAergic drug challenge. Together, these aims will use neuroimaging as a tool to establish the cross- over point to readiness for treatment. These objective indicators will improve our ability to plan treatment by permitting the clinician to predict the points at which an individual will be receptiv to a specific medication. Thus, one medication may be employed for abstinence initiation, and then once the brain has re-established GABAergic homeostasis, another medication can be used for relapse prevention. However, because not every treatment center has access to an imaging facility, a secondary goal is to evaluate the relationship between recovering GABA activity and cocaine-related cognitive impairments to determine the extent to which timed administration of a neuropsychological performance battery can predict GABAergic function. Our results will have the potential for high impact because the conceptual framework of brain readiness for treatment can be applied to drug dependence and psychiatry in general in order to provide a foundation for individualizing medicine.